Spring 2008

Scientific Article

Current Pathobiology, Prevention & Treatment
of Oral Mucositis: A Review
Shokofeh Motlagh - UNLV School of Dental Medicine Senior Student

Variable degrees of oral mucositis are present in 97% of head and neck cancer patients receiving conventional radiation therapy [1]. Mucositis significantly impacts patients’ nutrition and quality of life. Severe mucositis may lead to increased risk of opportunistic infections and may lead to sepsis and death. Mucositis causes interruptions in cancer treatment or reductions in planned radiation doses. More attention is now drawn to radiation induced mucositis as a consequence of its economic implications. In a recent review of patients with head and neck cancer who received radiation therapy, the rate of hospitalizations due to severe mucositis was as high as 50% for those treated with chemoradiotherapy [2]. Costs can accrue due to the need for parenteral nutrition, medications to treat infections and increased use of opioid analgesics. Another study estimated that the mean cost of mucositis treatment in head and neck cancer patients ranged from $2,954 to $4,037 per treatment [3]. As a result, intensive research has been performed to investigate the intricate pathobiology of mucositis which may lead to possible therapeutic interventions.

The Old Pathobiology Theory of Mucositis

Earlier pathobiology models postulated mucositis to arise solely as a result of epithelial injury. It was hypothesized that radiation or chemotherapy nonspecifically targeted the rapidly proliferating cells of the basal epithelium, causing the loss of the ability of the tissue to renew itself. The atrophy, thinning, followed by ulceration of the mucosal epithelium was thought to be a consequence of these events. As a result, until recently the therapeutic approach was solely targeted at epithelial stem cells [4].

Preliminary ideas regarding the mechanistic basis for mucositis were based solely on observational data. The histologic descriptions were limited to tissue obtained during autopsies of deceased cancer patients. It became clear that in order to investigate mucositis effectively, surrogate technology was necessary. Therefore, a quest for animal models began [2].

Emergence of Animal Models to Study Mucositis

Rather than simply using mouse models, the hamster became relevant for mucositis studies because of their large cheek pouch in which they store food. Hamsters also produce robust mucositis when the cheek pouch mucosa is irradiated. The oral bacterial flora is very similar to humans. Therefore, the availability of animal models coupled with clinical observations has opened doors to exploring the pathobiology underlying mucositis.

The old theory that mucositis is solely an epithelial process started to get questioned with sequential hamster studies. Oral mucosal biopsies were collected from hamsters at different times following mucosal irradiation causing mucositis. These biopsies were analyzed microscopically. Results showed damage to both blood vessel walls as well as well as connective tissue in the submucosa [5]. Even more importantly, the submucosal damage preceded epithelial injury by an entire week. [6] Similar results were met in the intestinal submucosa of mice. Further studies showed increased proinflammatory cytokines in the blood of mucositis patients. [7] These same blood results were met in the submucosa of hamsters as mucositis developed. Mucositis severity was reduced with the administration of a compound to suppress the cytokine production with no direct effect on the epithelium. [7] These research models increased the curiosity as well as awareness of the current pathobiology theory of mucositis.

Current Pathobiology Theory

Mucositis is believed to involve both direct and indirect mechanisms. Direct mucosal injury by radiation and chemotherapy interferes with the average five to fourteen day turnover time of the oral epithelium and causes premature apoptosis. [5] On the other hand, loss of salivary constituents and therapy induced neutropenia are believed to contribute to oral mucositis in an indirect fashion and promote the emergence of bacteria, fungi and viruses on damaged mucosa. There is a linear relationship among occurrence of oral mucositis and systemic granulocyte counts and a resolution of mucositis has been demonstrated with neutrophil recovery. [5] On the other hand, studies have also shown that significant mucositis occurs even in the absence of myelotoxicity. [6]

Based upon these findings, newer pathobiology concepts have emerged describing oral mucositis as a five stage process starting with an initiation phase, primary damage phase, signal amplification, an ulcerative/bacteriological phase, and lastly, a healing phase.

The initial stage of tissue injury is a very rapid process following administration of radiation or chemotherapy. The mucosa seems normal at this stage. However, there is both DNA and non-DNA damage present [8]. DNA strand breaks result in direct cellular injury that targets cells in both the basal epithelium and the submucosa. Simultaneously, reactive oxygen species are generated, mediating downstream biological events. Studies have shown that the destruction of submucosal cells is the largest contribution to injury at this stage followed by cell death in the in the basal and suprabasal epithelium [9].

The primary damage phase occurs as a result of the activation of transduction pathways that activate transcription factors such as p53 and NF-kB. NF-kB has been suggested to be one of the most significant transcription factors in terms of both toxicity and resistance of tumors to therapy [10]. Activation of NF-KB can result in the upregulation of up to 200 genes, many of which potentially have an effect on mucosal toxicity. Pro-inflammatory cytokines, including TNF-alpha, IL-1 beta and IL-6 are thought to cause damage either directly or indirectly by increasing vascular permeability thus enhancing the accumulation of cytotoxic drugs locally in the oral mucosa [11]. Signal amplification occurs as a consequence of the gene upregulation that is brought about by the initial activation of transcription factors. Some of the pro-inflammatory cytokines not only damage tissue but also provide a positive feedback loop to amplify the primary damage [12]. One example is TNF-alpha which will be

discussed further in the next section. Despite all the cellular injury, the clinical picture is quite normal with only slight erythema. Tissue integrity is in place and patients report few symptoms. This soon changes in the next stage of ulceration.

Ulceration is the most significant phase to both the patient and health care provider. Ulceration occurs one week after the initiation of radiation or chemotherapy. These extremely painful lesions are prone to bacterial and yeast infections. For neutropenic patients, these breaks in the mucosa serve as gateway for entry for numerous microorganisms that reside in the mouth and may lead to bacteremia and sepsis. Additionally, endotoxins and other baceterial metabolites result in respiratory bursts of mononuclear cells penetrate the submucosa and further enhance the release of inflammatory mediators, mainly IL-1, nitric oxide and TNFalpha. These mediators potentiate further tissue damage [12].

The healing phase usually lasts from day twelve to sixteen but may greatly vary. Some determining factors include epithelial proliferation rate, hematopoietic recovery, the microbial flora and the presence or absence of infection and mechanical irritations [11]. Signals from the submucosal extracellular matrix and the mesenchyme control the rate of epithelial-cell migration and the rate of proliferation and differentiation of healing tissue.

Clinical Manifestations of Mucositis

The earliest signs of mucositis include erythema and edema, a burning sensation, and an increased sensitivity to hot or spicy food. Erythematous areas may develop into white desquamative patches and subsequently into painful ulcers. The ulcers are portals of entries for bacterial, viral and most commonly fungal infections. Once secondarily infected, the ulcers are no longer asymptomatic. The pain and altered taste perception causes impaired nutritional and fluid intake, which interfere with the cancer treatment and impair the prognosis. The movable nonkeratinized mucosal surfaces are the most susceptible to mucositis. These include the soft palate, cheeks and lips, the ventral surface of the tongue, and the floor of mouth. On the other hand, the keratinized surfaces including the gingiva, dorsal surface of the tongue and the hard palate are rarely affected due to their slower rate of cellular turnover. Oral lesions usually disappear without scar formation unless there are serious complications involving infections and xerostomia [1].

Prevention and Treatment of
Oral Mucositis in Cancer Patients

While many interventions used for the treatment or prevention of mucositis have some evidence supporting their use, no intervention has been conclusively validated by research. Depending on the severity of mucositis as indicated in the toxicity grading table 1-1, different intervention categories have been recommended including general oral care protocols for the milder forms to antibacterial, antifungal and antiviral agents, mucosal barriers, mucosal cell stimulants, analgesics, topical anesthetics, immunomodulatory agents, mouthwashes with mixed action and cytoprotectants [11]. The Oral Care Protocol involves that all patients at risk of developing mucositis receive a standardized oral care regime as an ongoing component of their care. The aim of this regime is to limit opportunistic infection via the damaged mucosa. Preventive measures include treating all caries and dental diseases as well as oral hygiene instructions prior to any radiation and chemotherapy [5]. Post therapy treatment interventions involve rinsing mouth regularly, avoiding painful stimuli such as hot foods and drinks, spicy foods, alcohol and smoking, reporting any redness and tenderness or sores in the mouth or lips and prompt treatment of mucositis symptoms and oral infections [5]. For patients with head and neck cancer that are undergoing radiotherapy, prevention of mucositis involves benzydamines (mouthwash with anti-inflammatory, pain relieving, antimicrobial activities) and PTA lozenges (contain polymixin E, tobramycin and amphotericin B which together provide broad spectrum antibacterial and antifungal coverage) [12]. For the treatment of mucositis symptoms, benzydamine is also used as well as dyclonine HCL (topical anesthetic which involves viscous lignocaine with 1% cocaine and a solution containing kaolin-pectin, diphenhydramine and saline). On the other hand, if the patient is receiving chemotherapy with or without radiotherapy a different regiment is required. For prevention of mucositis in these patients, allopurinol and cryotherapy treatment is used for patients treated with 5-fluorouracil [12]. These are categorized under interventions which reduce the mucosal toxicity of chemotherapy drugs. The allopurinol is used as a mouthwash four to six or rapid cooling using ice causes local vasoconstriction and hence reduces blood flow to the oral mucosa. For cytotoxic drugs such as 5-FU which have a short half life and are administered sometimes as a bolus injection, cryotherapy may reduce the amount of drug reaching the oral mucous membranes and reduce mucositis caused by local cytotoxic activity of these drugs [5]. It imperative that oral health care providers are aware of the clinical manifestations and symptoms involved with mucositis and do a thorough medical questionnaire involving past and present radiation and chemotherapy. Routine dental work should be delayed until the symptoms of mucositis are resolved, depending on the toxicity grading involved. A thorough knowledge of oral manifestations of various systemic conditions is crucial for an oral health care provider in order to provide the utmost care for our patients.

About the Author
Shokofeh R Motlagh is currently a fourth year dental student at UNLV School of Dental Medicine in Las Vegas, Nevada. She would like to thank her mentors Dr. Herschaft & Dr. Simmons for the knowledge and enthusiasm they have provided her in the disciplines of oral medicine and oral pathology.

Table 1-1: Toxicity Grading of Oral Mucositis According to WHO and NCI-CTC
Criteria [6]

References

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2. Spielberger, R et al. Palifermin for Oral Mucositis after Intensive Therapy for Hematologic Cancers. The New England Journal of Medicine, 2004. 351 (25): p. 2590-2598.
3. Sonis, S.T. Oral Mucositis in Cancer Therapy. Supportive Oncology, 2004. 2(3) p. 3-8.
4. Scully, C. Sonis. S.T. & Diz, P.D. Mucosal Diseases Series. Oral Diseases Head & Neck Sciences, 2006. 12 (3) p. 229-241.
5. Prevention and Treatment of Oral Mucositis in Cancer Patients. Best Practice. Evidence Based Practice Information Sheets for Health Professionals, 1998. 2 (3).
6. Wolfgang J.K et al. Oral Mucositis Complicating Chemotherapy and/or Radiotherapy: Options for Prevention and Treatment. CA Cancer J for Clinicians, 2001. 51: p. 290-315.
7. Sesaki, M. et al. Differential regulation of metalloproteinase production, proliferation and chemotaxis of human lung fibroblasts by PDGF, IL-1B and TNF-alpha. Mediators Infl amm. 9: p. 155-160.
8. Koukourakis, M.I. Amifostine in clinical oncology: current use and future applications. Anticancer Drugs 2002. 13, 181-209.
9. Sonis, S. T. et al. An animal model for mucositis induced by cancer chemotherapy. Oral Surgery. Oral Medicine. Oral Pathology, 1990. 69, 437-443.
10. Sonis, S.T. et al. The gene expression sequence of radiated mucosa in an animal mucositis model. Cell Proliferation. 35, p.93-101.
11. Ferretti G.A. et al. Chlorhexidine prophylaxis for chemotherapy and radiotherapy induced stomatitis; a randomized double blind trial. Oral Surgery Oral Med Oral Pathology 1990. 69: p. 331-338.
12. Sonis, S.T et al. Oral Complications in patients receiving treatment for malignancies other than from head and neck radiation therapy. Cancer, 1992. 70: p. 2171-2180.

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